Prostate cancer is the 2nd leading cause of cancer death in males. As a result of screening with serum prostate specific antigen (PSA) there has been a dramatic increase in the number of men diagnosed with prostate cancer, about 220,000 new diagnoses annually. The diagnosis is being made at a younger age yet the morbidity of the standard treatment such as surgery and radiation---remain unchanged. Thus, men with the diagnosis of prostate cancer are likely being overtreated for their disease and will live with the consequences of this treatment for many years, greatly affecting the Quality of Life Years (QALY). The ultimate answer to this dilemma is serum biomarkers that identify lethal cancers but not incidental cancers but this is unlikely to occur soon. Indeed, recent studies show that the PSA screening test does not lead to improved outcomes. In the meantime, methods of localizing prostate cancer and treating them with minimally invasive therapy would dramatically lessen the morbidity associated with widespread screening and the overdiagnosis of prostate cancer. A variety of imaging methods have been developed and we are exploring their role in localizing early prostate cancer. The MIP has partnered with the Urologic Oncology Branch to develop new imaging methods to be coupled with minimally invasive treatment methods which include RF ablation, cryotherapy and alcohol ablation. The MIP is engaged in a number of pre-clinical studies in prostate cancer. We have been investigating a variety of targeted imaging agents. Initially, we have evaluated several antibodies and antibody fragments against PSMA (3TC, J591) in animal models of prostate cancer. Recently we began using PSMA PET based on small molecules that target PSMA. Metabolic studies of prostate cancer may have implications for therapy. We are investigating PET in animal models of prostate cancer to detect differences in metabolism between the androgen-sensitive and insensitive state. Moreover, we are launching a program in C13 hyperpolarization of pyruvate which will enable non invasive monitoring of metabolism Clinical Trials The MIP has been studying prostate cancer imaging in humans since its inception. We perform endorectal coil MRI at 3T . We have developed analytic tools for all in conjunction with a CRADA with the Philips Medical Systems. We have demonstrated that a multiparametric approach improves the specificity of 3T MRI for prostate cancer. However, there remain significant limitations in the sensitivity and specificity of 3T MRI. After patients undergo prostatectomy and their specimens are available for review it is clear that less than 40% would be amenable for focal therapy based on being single, well circumscribed lesions that are visible on MRI. We have designed a customized prostate mold which is in use in all patients at NCI. It enables the imaging to be directly correlated with the pathologic specimen. Therefore, working with Philips Medical Systems we have designed an US-MR fusion system that takes the data from the 3T MRI and fuses it to the real time ultrasound image. This product was released for sale in 2013 under the name UroNav. Biopsy and interventional procedures can then be performed under MR guidance using the ultrasound. This device has been used successfully in 1500 patients at NCI. A dog study showed the accuracy was about 3-4mm. We are currently using a similar platform to direct focal laser ablation (FLA) of suitable prostate lesions (i.e. ones that are well demarcated, low Gleason score and could otherwise be watched. We are also testing HIFU in animal models. Computer aided diagnosis and machine learning are new areas of research. We are searching for PET agents that might be more specific for prostate cancer, especially in detecting metastases. For instance, we completed a PET study using 11C-Acetate to study the value of this agent in identifying intraprostatic lesions. Patients also underwent 3T MRI and the PET image which were fused to the MRI. We have completed a trial using the tracer 18F-ACBC, an agent associated with amino acid transport which has shown success in localizing recurrent prostate cancer. Ultimately we wish to combine PET-MR studies and conduct minimally invasive therapies after US fusion. We have also been approved to test the agent, F18-DCFBC which is a low molecular weight tracer directed at PSMA. We are performing PET studies with a PSMA targeted PET agent. We are conducting trials using F18 DCFPyl, a second generation agent directed at PSMA. This agent has already shown great potential to characterize the disease status even when post treatment PSA levels are quite low. We are also generating computer aided diagnosis (CAD) devices and algorithms that could automate the diagnosis of prostate cancer.